Portable test apparatus and associated method of performing a blood coagulation test

ABSTRACT

A portable device for performing coagulation tests on a patient&#39;s blood. Blood is first drawn from a patient using a lancet. The blood is then supplied to a disposable cuvette placed within the testing device. The blood is drawn into multiple conduits within the cuvette. Each of the conduits contains a dried or lyophilized activation reagent that is rehydrated by the blood. The blood in each of the conduits is then reciprocally moved across a restricted region until a predetermined degree of coagulation occurs. Since the coagulation time is being monitored in multiple conduits, a representation coagulation time for a given sample can be determined. In at least one of the conduits a normalizing control agent is present. The normalizing control agent counteracts any effects of anticoagulants present in the blood sample, thereby allowing the blood sample to have generally normal coagulation characteristics. The normalized blood is tested simultaneously with the untreated blood to provide a reference value against which the functionality of the test system and the quality of the sample can be judged.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to portable devices for performing bloodcoagulation tests on blood such as a prothrombin time tests, and theassociated methods used to preform such tests.

2. Prior Art Statement

Many people with heart disease, venous thrombosis, history of strokesand the like are prescribed medications to reduce the coagulationcharacteristic of their blood. A commonly prescribed medication issodium warfarin isopropanol clathrate, generically known as warfarin andcommonly known by the brand name COUMADIN®, produced by DuPontPharmaceuticals of Wilmington, Del. Warfarin acts to inhibit thesynthesis of vitamin K dependent factors. The resultant effect in thebody of the patient is a sequential depression of blood Factors VII, IX,X and II. Upon the oral administration of warfarin, the anticoagulationeffect generally occurs within 24 hours. However, depending upon thepatient, the peak anticoagulant effect may be delayed 72 to 96 hours andits duration may persist for four to five days. Accordingly, it is knownthat warfarin is a potent drug with a half-life of approximately 21/2days, therefore the effects of warfarin on a patient may become morepronounced as daily maintenance doses overlap. Accordingly, due to thepotency of warfarin and its long lasting effects, it is critical thatthe level of warfarin in a patient be closely monitored. An overdose maycause spontaneous internal bleeding while an underdose would not be aneffective anticoagulant, resulting in thrombosis. Additionally, the needfor exact blood monitoring is more critical with warfarin than with manyother drugs because the relative effectiveness of warfarin is affectedby many other prescription and over-the-counter medications that may betaken by a patient using warfarin.

The most common manner of determining the effective amount of warfarinin a patient's blood is to preform a prothrombin time (PT) test. A PTtest measures how long a sample of blood takes to clot. As a result, theamount of anticoagulant in the blood can be calculated since theconcentration of anticoagulant is directly proportional to the length oftime required to form clots the blood sample.

The prior art is replete with various devices and methods for measuringthe coagulation time of blood samples. For example, such a method andapparatus is shown in U.S. Pat. No. 5,302,348 to Cusack et al., entitledBLOOD COAGULATION TIME TEST APPARATUS AND METHOD, which issued Apr. 12,1994 and is assigned to International Technidyne Corporation, theassignee herein. This patent shows a machine that measures thecoagulation time of blood placed in disposable cuvettes by pneumaticallymoving the blood through a single restricted passage in the cuvette.

U.S. Pat. No. 5,154,082 to Michael Mintz, entitledMICROPROCESSOR-CONTROLLED APPARATUS AND METHOD FOR DETECTING THECOAGULATION OF BLOOD, issued Oct. 13, 1992 and assigned to the assigneeherein, shows a device that measures blood coagulation by its effect ona ferromagnetic member in an electromagnetic field.

U.S. Pat. No. 4,797,369 which issued on Jan. 10, 1989 entitled METHODAND APPARATUS FOR DETECTING A BLOOD CLOT to Michael Mintz, and assignedto the assignee herein, shows the technique for measuring clot timewhereby a sample of whole blood or blood plasma is dispersed into two ormore zones. The zones are separated and brought together repeatedly,such that the blood sample is divided into multiple pans each associatedwith a zone. The pans are then rejoined into a single pan and theprocess of separation and joining continues. During the process, aliquid bridge between the separated parties is initially supported bysurface tension, but collapses at the point of maximum zonal separation.When a fibrin clot is entrained within the rejoined parts, it will alignin a direction parallel to the direction of the relative motion betweenthe zones. In this manner, a thread appears between the pans as they arebeing separated. This thread is indicative of a clot, wherein the whichclot is capable of being detected by visual or electrical means.

U.S. Pat. No. 3,486,859 entitled BLOOD ANALYZING METHOD AND APPARATUSissued on Dec. 30, 1969 to R. Greiner et al. This patent depicts a bloodanalyzing method and apparatus including a double arm holder havingblood liquid reactant chambers which communicate with each other via asmall capillary conduit. An air pump is provided for applying pressurechanges to one of the chambers to effect periodic mixing of the liquidsvia the capillary conduit. An indicator means is included to detect theprogressive restriction of the capillary conduit upon coagulation of theblood.

U.S. Pat. No. 3,695,842 entitled METHOD AND SYSTEM FOR ANALYZING ALIQUID issued on Oct. 3, 1972 to M. D. Mintz, and assigned to theassignee herein. The patent describes in detail a magnetically coupledmechanical blood clot detection system wherein a variable conductancedevice is disposed adjacent to a zone containing a liquid and a member.A predetermined variance in the conductance of the device is detectedupon change in magnetic flux lines when the liquid transforms itself andthe member is displaced. The signal is produced at the time thepredetermined variation in conductance has been detected.

An improved system means for measuring clotting time is disclosed inU.S. Pat. No. 3,836,333 entitled "SYSTEM FOR TIMING THE COAGULATION OFBLOOD" issued to Michael D. Mintz, on Oct. 30, 1972 and assigned toInternational Technidyne corporation, the assignee herein. Anelectromagnetic bias coil, which is wound around the reed switch,provides steady-state magnetic flux lines that supplement the flux linesprovided by the permanent magnet. When the density of the flux linespassing through the reed switch decreases, as a result of the magnetbeing displaced, the reed switch opens. The bias coil also provides amagnetic pulse, which forces the reed switch to a closed state. Thissystem is manufactured under the trademark HEMOCHRON® by InternationalTechnidyne Corporation at Edison, N.J.

U.S. Pat. No. 3,890,098 entitled MACHINE FOR THE DETERMINATION OFPROTHROMBIN TIME AND P.T.T. issued on Jun. 17, 1975 to E. Moreno. Thispatent describes a reactive material which is placed in a cup whichcommunicates with a second cup via a restricted orifice. Plasma isplaced in the second cup and the reactive material and plasma are movedfrom cup to cup by a pump until coagulation of the plasma takes place.Means are then provided for stopping the motion of the mixed reactivematerial and plasma. Other means are provided for measuring the timerequired for coagulation.

U.S. Pat. No. 3,951,606 entitled APPARATUS FOR PROTHROMBIN TESTINGissued on Apr. 20, 1976 to R. Moyer et al. This patent shows a manuallyoperable disposable device which can measure coagulation rates. Thedevice is a tube of a uniform bore which can accommodate a sample andcontains appropriate amounts of lyophilized reagents required to conductindividual tests such as that for prothrombin time. Calibration marks onthe tube are correlated in terms of these times and the position inwhich a liquid sample becomes immobilized as it descends down the tubecorresponds to the test time. The rate of descent of the liquid iscontrolled by a limiting orifice or constriction or by inclining thetube to the vertical axis.

U.S. Pat. No. 4,197,734 entitled APPARATUS FOR DETERMINING BLOODCLOTTING TIME issued on Apr. 15, 1980 to A. Rosenberg. This patentdescribes an apparatus which is capable of determining the clotting timeof blood. The apparatus includes a support frame which supports asyringe containing a blood sample and turntable adapted to rotate at anormal rate of speed. Blood from the syringe drops onto the turntablewhere the clotting time is automatically and graphically depicted by achart rotatively carried upon the turntable. The apparatus can also beemployed to determine variations in the viscosity of blood plasma andother fluids.

U.S. Pat. No. 4,725,554 entitled METHOD FOR MEASURING BLOOD COAGULATIONTIME issued on Feb. 16, 1988 to K. Schildkenecht. This patent shows amethod for measuring the coagulation time of a blood sample, in which asample reagent mixture is formed by introducing the sample and at leastone reagent into a cuvette. The sample reagent mixture is moved in astationary cuvette so that the mixture flows back and forth around anedge projecting in to the cuvette whereby a clot forms and is detectedon this edge.

U.S. Pat. No. 4,659,550 entitle METHOD AND APPARATUS FOR MEASURING BLOODCOAGULATION TIME is the parent of U.S. Pat. No. 4,725,554 andessentially describes the same system further utilizing photocelldetectors to determine a clot formation.

From the above-cited patents, it can be seen that many devices have beenmade that are capable of performing a coagulation time test. However,most of these prior art devices are designed for use in a medicallaboratory environment. Few of these devices are portable and simpleenough to operate by a patient in his or her home. Furthermore, theprior art devices only provide the user with a single test result forthe current blood sample. None of the cited references are capable ofanalyzing the current blood sample in view of previously stored resultsin order to provide a historical analysis and a means to havestatistical process control over the long time use of warfarin.

One of the most difficult aspects of using the cited prior art testdevices is the taking of the blood sample from the patient and theadministration of the blood sample to the testing equipment. In manycases, the taking of blood requires a syringe or evacuated tube and theadministration of the blood to the test equipment requires complexmeasurements and the use of pipettes. Obviously, such devices are notintended for unassisted home use.

A need therefore exits in the art for a portable, reliable and accurateself contained blood coagulation testing device that is simple to useand can be used at home by an unassisted patient.

The need also exists in the art for a blood coagulation testing devicethat has a simple means of donating the blood sample from the patientand properly administering the blood sample to the testing device.

A further need exists for a personal blood coagulation testing devicethat stores multiple readings from a single patient over a given periodof time and presents a historical analysis of a current test.

These needs are provided for by the present invention as described andclaimed below.

SUMMARY OF THE INVENTION

The present invention is a self contained, portable device forperforming blood coagulation tests on a patient's blood. Blood is firstdrawn from a patient using a lancet. The blood is then supplied to adisposable cuvette placed within the testing device. The blood is drawninto multiple conduits within the cuvette. In a preferred embodiment,each of the conduits contain a dried prothrombin time reagent that isrehydrated by the blood. The blood in each of the conduits is thenreciprocally moved across a restricted region until a predetermineddegree of coagulation occurs. Since the coagulation time is beingmonitored in multiple conduits, a median coagulation time for a givensample can be determined.

In at least one of the conduits a normalizing control agent is present.The normalizing control agent counteracts any effects of warfarinpresent in the blood sample, thereby allowing the blood sample to havegenerally normal coagulation characteristics. The normalized blood istested simultaneously with the untreated blood to provide a qualitycontrol reference value against which the quality of the reagents andthe functionality of the system can be judged. The normalizing controlagent is capable of normalizing the effects of warfarin in a bloodsample across a large range of clotting factor differences. Thenormalizing control agent includes Vitamin K clotting factorconcentration purified from normal plasma, barium citrate eluate,gluconic acid, buffers and stabilizers.

Another reference value is obtained by placing an anticoagulant in oneof the cuvette conduits to produce an abnormal control agent. Theabnormal control agent is also tested simultaneously with the untreatedblood to provide a second quality control reference value against whichthe upper range of coagulation times can be judged.

BRIEF DESCRIPTION OF THE DRAWINGS

For a better understanding of the present invention, reference is madeto the following description of exemplary embodiments thereof,considered in conjunction with the accompanying drawings, in which:

FIG. 1 is a perspective view of one preferred embodiment of the presentinvention cuvette and blood coagulation testing apparatus;

FIG. 2 is a top view of one preferred embodiment of the presentinvention cuvette;

FIG. 3a is a cross-sectional view of the embodiment of the cuvette shownin FIG. 2, viewed along section line 3--3;

FIG. 3b is a cross-sectional view of the embodiment of the cuvette shownin FIG. 2, viewed along section line 3--3, and shown in conjunction witha lanced finger supplying blood to the cuvette;

FIG. 4a is a cross-sectional view of a segment of the blood coagulationtime testing apparatus shown in FIG. 1;

FIG. 4b is the same cross-sectional view as is shown in FIG. 4a with theaddition of having a cuvette inserted into the blood coagulation timetesting apparatus;

FIG. 5 shows a top view of the present invention cuvette shortly afterblood is drawn into each of the five conduits contained within thecuvette;

FIGS. 6a-6i show the cycle of the flow of blood in the cuvette past theelectrooptical sensors;

FIG. 7a shows a person using a lancet to obtain a blood sample from afinger;

FIG. 7b shows the blood sample on the finger being supplied to thecuvette within the blood coagulation test apparatus;

FIG. 8a shows a person using a specialized lancet to obtain a bloodsample from a finger;

FIG. 8b shows the blood sample on the finger being supplied to areservoir built into the lancet;

FIG. 8c shows the lancet being supplied to the blood coagulation testapparatus above the cuvette;

FIG. 8d shows a selective cross-sectional view of the lancet as it isapplied to the test apparatus;

FIG. 8e shows the lancet engaging the test apparatus;

FIG. 9a shows a blood sample collection attachment that can beselectively joined to a lancet;

FIG. 9b shows the blood sample on a finger being supplied to the bloodcollection attachment when coupled to a lancet;

FIG. 9c shows a segment cross-sectional view of FIG. 9b, viewed alongsection line 9c--9c;

FIG. 9d and 9e show the lancet and blood collection attachment beingapplied to a testing device;

FIG. 10 shows an isolated view of a disposable sample cup; and

FIG. 11 shows a perspective view of the pneumatic system of the testingdevice.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is an apparatus and method for determining thecoagulation time for the blood of a patient, especially a patient who istaking an anticoagulation drug such as warfarin. Referring to FIG. 1,there is shown one preferred embodiment of the present inventionapparatus 10. The apparatus 10 is a self-contained portable testinginstrument designed to provide a simple, user friendly blood coagulationanalysis, i.e. prothrombin time (PT) test, to either the user or theuser's physician. In the shown embodiment, the apparatus 10 consists ofa disposable cuvette 12 and the actual testing device 14. To utilize thepresent invention apparatus 10, a sample of blood 16 is placed withinthe cuvette 12. The disposable cuvette 12 is inserted into the testingdevice 14 through slot 20. The testing device 14 tests the blood sample16 within the disposable cuvette 12 without contacting the blood sample16. Accordingly, once the PT test has been completed, the cuvette 12 canbe removed from the testing device 14 and disposed. Another cuvette canthen be entered into the testing device 14 without the need to sterilizeor otherwise clean the testing device 14.

A display 24 is disposed on the top of the testing device 14. As will belater be explained, the display 24 can display either the results of atest just preformed, or may display a historical analysis of previouslystored test results. Various control buttons 25, 26, 27 are alsodisposed on the testing device 14 for the purpose of starting thedevice, controlling the display and accessing stored data from memory.

Referring to FIG. 2 there is shown a top view of one preferredembodiment of the disposable cuvette 12. The cuvette 12 has asubstantially planar structure made from a transparent material. Withinthe cuvette 12 are five channels or conduits 30, 31, 32, 33, 34. Thenumber five is preferred, however fewer or greater numbers of conduitscould be used. The distal ends of each of the five conduits 30, 31, 32,33, 34 terminate at drive apertures 35 that extend through the uppersurface 36 of the cuvette 12. The ends of each of the conduits 30, 31,32, 33, 34 opposite the drive apertures 35 each terminate a commonsupply area 37 contained within the cuvette 12. Blood is supplied to thecommon supply area 37 by a supply conduit 38 that selectively couples toa supply reservoir 40 in a manner that will be later explained. Each ofthe conduits 30, 31, 32, 33, 34 within the cuvette 12 contains arestricted area 42 where the internal area of the conduit rapidlynarrows, The internal surface of the restricted areas 42 inside each ofthe conduits 30, 31, 32, 33, 34 is preferably roughened or otherwisetextured to promote the coagulation of blood in the restricted areas 42as blood travels through the various conduits 30, 31, 32, 33, 34.

A clot promoting reagent 28 is disposed in each of the conduits 30, 31,32, 33, 34 within the cuvette 12 in between the restricted areas 42 andthe drive apertures 35. The clot promoting reagent 28 is a prothrombintime reagent such as dried rabbit brain thromboplastin at approximately30 mg/ml, however other clot promoting reagents can be used, such astissue factor. The dried control agent 28 is placed within each of theconduits 30, 31, 32, 33, 34 wherein presence of blood in the conduitsrehydrates the clot promoting reagent 28, thereby mixing the clotpromoting reagent 28 with the blood. The thromboplastin reagent ispreferably dried by a water extraction technique such as lyophilizationwithin the conduits 30, 31, 32, 33, 34. The middle three conduits 31,32, 33 are the sample test conduits that will be used for the actualblood sample analysis. The first conduit 30 is an abnormal controlchannel and the last conduit 34 is a normal control channel. In themiddle three conduits 31, 32, 33 the blood sample tested and the resultsare averaged to ascertain the actual analytical value of the sample. Aswill be explained, in the normal control channel 34 the blood sample isnormalized prior to reaching the restricted area by the blood passingthrough an appropriate normal control agent 29. The normalized blood isthen tested to provide the testing device with a normal blood sample forreference.

The normal control agent 29 preferably consists of an air dried mixture,containing at least one Vitamin K dependent clotting factorconcentrates, barium citrate eluate, barbital buffered saline,trehalose, malto dextrin and thimerosal. The Vitamin K dependentclotting factors concentrates are obtained through a fractionationtechnique, employing column chromatography which may be performed inconjunction with selected protein absorbs (i.e. barium citrate). Suchtechniques are known in clinical hematology. The Vitamin K dependentfactor concentrates are prepared from human pooled plasma with orwithout bovine pooled plasma. Several manipulations in the manufactureof the normal control agent 29 result in a stable preparation. Thesemanipulations includes adding the two Vitamin K dependent factorconcentrates and barium citrate eluate separately to a plasma with adifferent degree to find out the concentrations of the two coagulationfactor concentrates that will bring the abnormal plasma to a normal orclose to normal prothrombin time. The two coagulation factorconcentrates are then mixed and buffered, and both stabilizers andthimerosal are added. The concentration is then adjusted and the reagentis air dried and packaged.

The normal control agent 29 may also contain gluconic acid, calciumsalts and heparin to decrease or increase coagulation clotting time.However, the preferred normal control agent 29 composition is asfollows:

    ______________________________________         Vitamin K         Dependent         Clotting                  Treha-         Factor     Eluate   GAC   lose  M700  BBS    ______________________________________    Min  1.0 u/ml   .009 u/ml                             .008 M                                   3.0%  2%    buffer    Max  3.5 u/ml   .035 u/ml                             .03 M 8.0%  6%    buffer    ______________________________________

One example of a Vitamin K dependent clotting factor concentrate is aFactor IX complex (Konyne 80), purchased from Miles Inc. The Eluate isbarium citrate eluate, purchased from Sigma Chemical Company. The GAC isgluconic acid with calcium salts, purchased from Sigma Chemical Company.The Trehalose is purchased from Sigma Chemical Company. The M700 isMalto dextrin, purchased from Grain Processing Corporation. Finally, theBBS is Barbital, sodium salt, purchased from Sigma Chemical Company.

In the first conduit 30, within the cuvette 12, an abnormal controlagent 39 is disposed between the restricted area 42 and the commonsupply area 37. The abnormal control agent 39 is rehydrated by the bloodin the first conduit 30, wherein the abnormal control agent 39 mixeswith the blood and provides the blood with known abnormal clottingcharacteristics. The composition of the abnormal control agent 39 ispreferably the same as the composition of the normal control agentpreviously listed with the addition of between 0.5 u/ml and 3.0 u/ml ofheparin, with or without the elimination of the GAC. As will beexplained, the blood in the first conduit 30 that mixes with theabnormal control agent 39 is tested simultaneously with the blood in themiddle three conduits 31, 32, 33 and the normalized blood in the lastconduit 34. The testing of the abnormal sample assures the quality andintegrity of the blood sample used in determining the test results ofthe middle three conduits 31, 32, 33. The use of a normal sample, anabnormal sample and multiple test samples enables the clotting timeperformance of the sample blood to be accurately evaluated irrespectiveof the clotting characteristics of the blood sample being tested.Accordingly, the effect of the anticoagulation drug in the blood can beaccurately measured despite the effects of other drugs or thecoagulation characteristics of the patient's blood prior to theadministration of the anticoagulant. Testing the normalized blood inconduit 34 and the abnormal blood in conduit 30, assures that the bloodsample collection, the test reagents employed in the cuvette and thetesting instrument are all within the preestablished performancespecifications. This level of internal quality control assures thehealth care provider (i.e. patient physician) that the prothrombin timetest results accurately reflect the level of patient's bloodcoagulation.

Referring to FIG. 3a in conjunction with FIG. 2 it can be seen thatsupply reservoir 40 on the cuvette 12 is a cup-like structure having anopen top 44 and a small aperture 45 on its bottom surface 46. In theshown embodiment, the supply reservoir 40 is supported at an anglerelative to the horizontal by a flexible pawl 48. The supply reservoir40 also is coupled to the cuvette 12 by a small protrusion 49 thatenters a recess 47 disposed within the material of the cuvette 12. Belowthe supply reservoir 40 is an opening 51 that leads to the supplyconduit 38. Referring to FIG. 3a in conjunction with FIG. 3b it can beseen that a blood sample is administrated to the supply reservoir 40 bya person pricking his/her finger and placing the pricked finger over thesupply reservoir 40. The weight of the finger on the supply reservoir 40causes the flexible pawl 48 to yield. This causes the supply reservoir40 to pivotably rotate into a horizontal position as guided by the pivotthat is created by the presence of the protrusion 49 in the recess 47.As the supply reservoir 40 rotates into the horizontal, the aperture 45on the bottom surface 46 of the supply reservoir 40 aligns and abutsagainst the opening 51 that leads to the supply conduit 38. Once alignedand in abutment, low pneumatic pressure in the supply conduit 38 drawsblood out of the supply reservoir 40 and into the supply conduit 38.During such a transition, the person's finger is covering the open top44 of the supply reservoir 40. In order to prevent a vacuum from formingin the supply conduit 38, a vent aperture 53 is formed in the wall ofthe supply reservoir 40, below the finger. This allows air to flow intothe supply reservoir 40, thereby preventing any back pressure fromrestricting the flow of blood out of the supply reservoir 40. As willlater be explained, the placement of a finger on the cuvette is only oneway of filling the cuvette with a blood sample. In alternate embodimentsblood can be transferred to the cuvette in a sample cup or a customizedlancet, both of which will be later described.

To use the present invention, a clean cuvette 12 is placed with the testdevice 14 (FIG. 1). Referring to FIG. 4a it can be seen that a testinginterface unit 50 is disposed within the testing device 14. The cuvetteenters the test device 14 via the slot 20. The slot 20 leads into achannel 54 shaped to receive the cuvette within the testing interfaceunit 50. Below the channel 54 is positioned a heating element 56 such asa foil heater or the like which is used to heat the cuvette when it iswithin the channel 54. At the distal end of the channel 54, opposite theentrance slot 20, are positioned a proximity switch 58 and a pneumaticmanifold assembly 60. The pneumatic manifold assembly 60 consists offive manifold members 62 of which only one is shown in FIGS. 4a and 4b.Each manifold member 62 is pneumatically coupled to a tube 64. The tubes64 lead to pneumatic sources (not shown) capable of periodicallysupplying both positive and negative pressures relevant to the ambientpressure. A rocker arm member 66 extends downwardly from each themanifold members 62. Each manifold member 62 has an orifice formedthrough its structure through which an axle rod 68 may pass.Consequently, the whole pneumatic assembly 60 is pivotably rotatablearound axle rod 68. At the base of each manifold member 62 is positionedan elastomeric seal 70 having a central orifice 74. The central orifice74 pneumatically communicates with the manifold member 62 and therespective tubes 64 that lead to the pneumatic sources.

Proximate the center of the channel 54 are positioned a plurality ofphotoelectric sensors 61 positioned on one side of the channel 54directly across from light sources 53 which may be incandescent bulbs,light emitting diodes or the like. In the preferred embodiment threephotoelectric sensors 61 are used, however additional photoelectricsensors may be added. As will be later explained, the photoelectricsensors 61 and light sources 53 are positioned within the testinginterface unit 50 at positions that correspond to the five conduits 30,31, 32, 33, 34, 35 (FIG. 2) in the cuvette 12 when the cuvette 12 isplaced within the testing interface unit 50. As such, light emissionsfrom the light sources 53 to the photoelectric sensors 61 must passthrough to a material of the cuvette 12, the conduits 30, 31, 32, 33, 34and the material contained within the conduits 30, 31, 32, 33, 34. Aforth photoelectric sensor 41 and light source 43 are disposed at thefar end of the channel 54. The fourth photoelectric sensor 41 and lightsource 43 serve as a fail safe detector that prevents blood from beingdrawn into the manifold member 62.

In FIG. 4b the testing interface unit 50 of FIG. 4a is depicted incombination with the cuvette 12. As can be seen, when the cuvette 12 isinserted into the channel 54, the cuvette 12 rotates the pneumaticmanifold assembly 60 around the axle 68. Consequently, the elastomericseals 70 on each of the manifold members 62 rotate against the materialof the cuvette 12. As the elastomeric seals 70 rotate and contact thecuvette 12, the orifice 74 on the elastomeric seal 70 aligns with thedrive aperture 35 of the corresponding conduit in the cuvette 12. Thecontact between the elastomeric seals and the cuvette 12 create an airtight seal, as such each of the manifold members 62 becomespneumatically coupled to a corresponding conduit 30, 31, 32, 33, 34within the cuvette 12.

The placement of the cuvette 12 fully within the testing interface unit50 positions the restricted areas 42 and surrounding regions of the fiveconduits above the heating element 56. Consequently, blood containedwithin the cuvette 12 can be raised to, and maintained at, apredetermined temperature for testing, despite variations in thesurrounding ambient temperature or the original temperature of thecuvette 12. The placement of the cuvette 12 within the testing interfaceunit 50 also positions the restricted areas 42 of the five conduits 30,31, 32, 33, 34, proximate five corresponding sets of photoelectricsensors 61. Consequently, the presence of blood in any one of theconduits 30, 31, 32, 33, 34, can be detected on the supply side of therestricted areas 42 in each of the conduits by the photoelectric sensors61. Furthermore, the placement of the cuvette 12 fully into the testinginterface unit 50 causes a bar code or other indicia to be read by ascanner. This identifies the curvette and notifies a central controlunit that a cuvette 12 has been entered into the test device 14 fortesting.

Referring now to FIG. 5 in conjunction with FIG. 4b, the operation ofthe present invention can be described. To begin a blood coagulationtime test on a sample of blood, the cuvette 12 is inserted into the testdevice 14. Once in place, the supply reservoir 40 is filled with asample of blood in a manner which will be later explained. Once insertedin to the test device 14, the five conduits 30, 31, 32, 33, 34 becomepneumatically coupled to the manifold assembly 60 and a pneumatic source87 coupled to the manifold assembly 60 by the tubes 64 (FIG. 4b), in themanner previously described. In FIG. 5, a newly inserted cuvette 12 isshown where the sample of blood is newly drawn from the sample reservoir40, by pneumatic pressures that are applied to the five conduits 30, 31,32, 33, 34. As such, the blood is drawn out of the sample reservoir 40,through the supply conduit 38 and an equal amount is drawn into each ofthe five conduits 30, 31, 32, 33, 34.

The sample reservoir 40 is capable of retaining at least one hundredmicro liters of blood from the patient's fingertip. Once the cuvette 12is properly placed in the testing device, the pneumatic source 87 reducethe pressure within the five conduits 30, 31, 32, 33, 34. The lowpressure is maintained until ten microliters of blood are drawn intoeach of the five conduits 30, 31, 32, 33, 34. As the blood in the normalcontrol conduit 34 and the abnormal control conduit 30 are drawn towardthe restricted areas 42 in each conduit, the blood rehydrates the normalcontrol agent 29 and the abnormal control agent 39, respectively,present within those conduits. In these two conduits, the blood sampleis therefore altered prior to the blood sample traversing the restrictedareas 42. As the blood sample travels through each of the conduits 30,31, 32, 33, 34 passes across the optical array of the threephotoelectric sensors 61. As the blood sample crosses the photoelectricsensors 61 for the first time the sensors 61 can be used to measuresample size and sample position relative to one another and relative tothe expected position as determined from the pneumatic source 87.

The pneumatic source cycles back and forth causing the blood sample ineach of the conduits 30, 31, 32, 33, 34 to reciprocally flow pass therestricted region 42. As the blood sample in each of the conduits 30,31, 32, 33, 34 begins to coagulate, fibrin forms and occludes therestricted regions 42 within the conduits 30, 31, 32, 33, 34. Theocclusions eventually stop or substantially slow the flow of blood. Inthe process of pumping the blood sample past the restricted region 42,the process of fibrin formation can be disrupted by the velocity changeof the blood as it enters the smaller diameter restricted region 42.This disruption is especially significant in highly anticoagulatedspecimens. In order to compensate for the velocity change the cycledflow of the blood sample is decreased over time in order to allowadditional time for clots to form in the unrestricted portions of theblood sample. The decrease is implemented on a time weighted basis suchthat the system resolution can be optimized to a percentage of totalelapsed time. For example, continuously decreasing the rate ofoscillation by 5% enables one to resolve fast forming clots withinfractions of a second and resolve slow forming clots of highlyanticoagulated samples well within the overall test time.

Referring to FIGS. 6a-6i, the actual testing cycle is illustrated. Theblood sample is drawn past the three photoelectric sensors 61 into therestricted region in each of the conduits present within the cuvette.Once drawn through the restricted region the blood sample rehydrates andmixes with the clot promoting reagent 28 (FIG. 2) present within each ofthe conduits. In FIG. 6a the blood sample is shown within the restrictedregion 42 but not obstructing any of the three photoelectric sensors 61.As such, the three photoelectric sensors 61 produce a (0,0,0) signal asindicated in FIG. 6a. When the blood sample is clear of the threephotoelectric sensors 61 and is within the restricted region 42, acounting cycle is begun on an internal clock 89 (FIG. 5). The pneumaticsource 87 reverses and pushes the blood sample through the restrictedregion and back toward the three photoelectric sensors 61. As can beseen in FIGS. 6b, 6c and 6d, the first photoelectric sensor becomesobscured as does the second and third photoelectric sensor in turn. As aresult, the signal received from the photoelectric sensors 61 changesfrom (0,0,0) to (1,0,0) to (1,1,0) and finally (1,1,1) once all thephotoelectric sensors 61 are obscured. Once the (1,1,1) signal isreceived by the C.P.U. 88 (FIG. 5) the pneumatic source 87 is reversedand the blood is drawn back through the restricted region 42. In FIGS.6e, 6f, 6g and 6h it can be seen that once the pneumatic source 87 isreversed the signal received from the photoelectric sensors 61 changefrom (1,1,1) to (1,1,0) to (1,0,0) and finally back to (0,0,0). Once the(0,0,0) signal is received by the CPU 88 (FIG. 5), the pneumatic source87 is again reversed and the cycle is repeated.

Returning to FIG. 5, it will be understood that as the cycles ofmovement repeat the blood sample begins to coagulate in the restrictedareas 42 of the five conduits 30, 31, 32, 33, 34. The coagulation ispromoted by the roughened surfaces each of restricted areas 42. As such,with each cycle the occlusion presented by the restricted areas 42increases. Consequently, one coagulation has begun, each cycle takesmore time than the previous since the opening being traversed by theflowing blood sample becomes smaller. At the same time, the rate atwhich the column of blood is oscillated or driven back and fourth isdecreased. The decrease is implemented on a time weighted basis suchthat the system resolution can be optimized to a percentage of totalelapsed time.

For each cycle the CPU 88, via internal clock 89, counts the time forthe cycle and compares it to the previously cycle time. When any onecycle time is a predetermined amount of time longer than the previouscycle time, the CPU 88 considers coagulation to have occurred and theoverall time for coagulation is displayed. For example, in one preferredembodiment of the present invention, it has been determined that asubstantial change between subsequent cycle times indicates coagulationhas occurred. As such, if one cycle took four seconds and the next cycletook five seconds, the CPU 88 would stop the test and display theelapsed time taken for coagulation to occur. However, each of the fiveconduits is monitored independently. As a result, the results of thetest are not displayed until coagulation has occurred in all of theconduits and the actual test results are calculating the CPU 88.

As can be seen from FIGS. 4b and 5, the cuvette 12 passes under a barcode scanner 90 when inserted into the testing device 14. A bar code 91is disposed on each cuvette 12. The first purpose of the bar code 91 isto inform the testing device as to which type of test is beingpreformed, i.e. PT, APTT, etc. The bar code 91 identifies reagentstandardization parameters that correspond to variations between lotssuch as the ISI valve for PT reagent. The bar code 91 can also preventexpired cuvettes from being tested by identifying the point ofexpiration for the various dried reagents contained within the cuvette.The passage of the bar code 31 under the bar code scanner 90 shows thatthe cuvette is properly placed within the testing machine and may alsoautomatically start the testing sequence.

The use of a bar code and a bar code scanner is only exemplary and itwill be understood that any optical or electronic identification systemcan be used in place of the bar code system.

In the preferred embodiment of the present invention test device, theCPU 88 is capable of retaining the results of at least ten differenttests in memory for a given patient. For any one given test, thecoagulation time result is compared to a predetermined maximum value anda minimum value. If the test results fall outside the acceptable range,a warning is displayed to make the patient and/or the doctor aware ofthe danger. The test device 14 may also include a modem jack 95 (FIG. 1)that enables the test device 14 to download information stored in memoryover the telephone. A patient, using the test device 14 at home, canthereby send test data to a doctor or a hospital over the telephone.

In the preferred method of use, the blood sample used in testing isobtained from a finger prick. Referring to FIG. 7a it can be seen thatthe finger prick is preferably made by a TENDERLETT® lancet 101, asdisclosed by U.S. Pat. No. 5,133,730 to Biro et al entitledDISPOSABLE-RETRACTABLE FINGER STICK DEVICE, and assigned toInternational Technidyne Corporation, the assignee herein, thedisclosure of which is herein incorporated by reference. After theTENDERLETT® device is used to create the finger prick, the initialdroplet of blood is wiped clean of the finger. An alcohol pad and gauzemay be included in each test kit with the lancet to promote the propercollection technique. A second droplet of blood is then allowed to formon the finger. Referring to FIG. 7b it can be seen that the droplet ofblood 100 is then directed into the sample reservoir 40 on the cuvette12. The blood is then drawn into the cuvette 12 in the manner previouslydescribed.

Referring to FIG. 8a the lancet 102 is used to cut a patient's finger.The lancet 102 has two modifications not currently found in aTENDERLETT® lancet. Those modifications include a funnel shaped aperture104 that extends through the lancet 104 and a guide protrusion 105 thatextends below a bottom surface of the lancet 102. Referring to FIG. 8dit can be seen that the funnel shaped aperture 104 has a large topopening 106 and a small bottom opening 107. The small bottom opening 107is small enough so that the surface tension of blood added to theaperture 104 prevents the blood from flowing through the small bottomopening 107 unassisted. As is shown in FIG. 8b and 8c a blood sample 108is taken from the lanced finger and is placed in the large top opening106 of the funnel shaped aperture 104. The lancet 102 has a ledge 109disposed at one end that engages an overhang 110 extending from the testmachine 114. Referring to FIGS. 8d and 8e it can be seen that thecuvette 112 does not have the sample reservoir as previously described,but rather has a nipple region 113 that partially passes into theaperture 104 on the lancet 102 as the lancet 102 is laid upon thecuvette 112. Once laid into place, the blood in the aperture 104 can bedrawn into the cuvette 112 by a pneumatic pump as was previouslydescribed.

Referring to FIG. 9a there is shown a blood sample reservoir attachment120 that can be attached to a TENDERLETT® lancet. The attachment 120includes a slotted region 122 that engages the exterior housing of aTENDERLETT® lancet. A conical shaped reservoir 124 is supported by theattachment 120. The attachment 120 is preferably a disposable devicethat can be selectively added to a standard TENDERLETT® lancet. However,in an alternative embodiment, the attachment 120 and lancet can beintegrally formed. Referring to FIGS. 9b, 9c, 9d and 9e it can be seenthat the reservoir attachment 120 is added to a TENDERLETT® lancet 121,wherein the TENDERLETT® lancet is used to create a finger prick. Theblood from the prick is then added to the conical shaped reservoir 124as is shown in FIG. 9b. The entire TENDERLETT/blood sample reservoirattachment 120 is then placed into a slot 132 in the testing device 140.The conical shaped reservoir 124 aligns over an aperture in the cuvette142, whereby blood can be drawn into the cuvette 142 from the conicalshaped reservoir 124. As is shown in FIG. 9c the conical shapedreservoir 124 has a narrow channel 125 at its bottom that serves todrain the blood sample from the reservoir 124. The diameter of thenarrow channel 125 is small enough so that the surface tension of theblood sample prevents the blood from draining through the narrow channel125 unassisted. From FIGS. 9d and 9e, it can be seen that as theTENDERLETT® lancet 121 and the reservoir attachment 120 are added to thetesting device 140, the conical shaped reservoir 124 aligns over anaperture 126 in the cuvette 142. The blood sample can then be drawn intothe cuvette 142 from the conical shaped reservoir by creating a negativepressure in the cuvette 142.

In the embodiment of FIGS. 9a-9e, the reservoir attachment 120 is shownas a detachable piece that is separate from the lancet 121. Since boththe lancet 121 and the reservoir attachment 120 are disposable items, itwill be understood that the reservoir attachment 120 can be madeintegral with the lancet, wherein separation of the two components wouldnot be possible.

Referring to FIG. 10 an alternate device for collecting blood is shown.In FIG. 10 a disposable, inexpensive collection cup 130 is shown thatcan be used in place of the reservoir attachment previously described.The collection cup 130 defines a conical shaped reservoir 131 into whicha sample of blood can be placed. A narrow channel 132 extends downwardlyfrom the bottom of the conical shaped reservoir 13 1, wherein blood isto viscous to flow through the narrow channel 132 unassisted. A handletab 133 radially extends from the collection cup 130. The handle tab 133provides a surface that can be readily gripped by a person, whereby thecollection cup 130 can be filled with blood and placed in a testingdevice. The collection cup 130 is filled with a blood sample and placedover a cuvette in a testing machine, such as is shown in FIG. 9d. Thecollection cup 130 is manipulated so that the narrow channel 132 alignsover the aperture in the cuvette, whereby the blood can be drawn fromthe collection cup by creating a negative pressure in the cuvette 142.

Referring to FIG. 11 it can be seen that regardless of whether blood isintroduced into the cuvette supply orifice by finger 151, collection cup152 or lancet/reservoir assembly 153, the blood sample is drawn into theconduits 30, 31, 32, 33, 34 within the cuvette by the creation of a lowpressure condition within the conduits 30, 31, 32, 33, 34. Although anypneumatic means can be used to create the low pressure condition, thepreferred pneumatic means is a stepped motor 155 and a positivedisplacement pump array 156. The positive displacement pump array 156consists of five pump pistons 157, wherein a different pump piston 157is coupled to each of the conduits 30, 31, 32, 33, 34 in the cuvette.Each of the five pump pistons 157 is driven by a ganged drive 159 thatis displaced by the motor 155. As a result, the change in pressure isthe same in each of the five conduits 30, 31, 32, 33, 34 as the motor155 moves the ganged drive 159.

It should be understood that the embodiment described herein is merelyexemplary and that a person skilled in the art may make many variationsand modifications to the described embodiment utilizing functionallyequivalent components to those described. More specifically, it shouldbe understood that any shaped and constructed conduit path can be usedin reciprocally cycling the blood test sample. As such, the placement ofphotoelectric sensors and the time differential between cycles needed todetermine coagulation may vary. One may utilize only one photosensor todetect the presence of clotted blood. As one can ascertain, upon theformation of a clot, blood would not move through the constricted areaand hence the sensor would not change state. The composition of thenormalizing reagent, abnormal reagent and control agent can also bemodified utilizing equivalent chemical compounds. All such equivalentcomponents, variations and modifications are intended to be includedwithin the scope of this invention as defined by the appended claims.

What is claimed is:
 1. A method of performing a prothrombin time test ona blood sample that contains an anticoagulant, comprising the stepsof:providing a plurality of conduits that extend from a first end to asecond end, wherein at least one restriction is disposed between saidfirst end and second end in each of said conduits, said plurality ofconduits including at least one test conduit and at least one controlconduit; providing a normalizing agent in said at least one controlconduit, wherein said normalizing agent is capable of counteractingeffects of the anticoagulant in the blood sample; drawing apredetermined volume of blood into each of said plurality of conduits;simultaneously moving the blood in each of said plurality of conduitsback and forth through said at least one restriction from a firstposition to a second position, wherein said normalizing agent in saidcontrol conduit mixes with the blood and creates a normalized bloodsample; timing how long it takes the blood in each of said test conduitsto move from said first position to said second position, until apredetermined degree of coagulation occurs; analyzing the coagulationtimes occurring in said test conduit, to obtain a representativeprothrombin time for the blood sample; and using the normalized bloodsample in the control conduit as a quality control sample to quantifythe reliability of the prothrombin time test for the blood sample. 2.The method according to claim 1, further including the step of mixingthe blood in each of said plurality of conduits with a prothrombin timereagent.
 3. The method according to claim 2, wherein said prothrombintime reagent is selected from a group including thromboplastin extractand tissue factor.
 4. The method according to claim 1, further includingsteps of:mixing the blood in one of said plurality of conduits with ananticoagulant, thereby creating an abnormal blood sample with abnormalcoagulation characteristics; using the abnormal blood sample in theprothrombin time test as a quality control sample to quantify thereliability of the prothrombin time test for the blood sample.
 5. Themethod according to claim 1, wherein said normalizing agent includesVitamin K dependent clotting factor concentrate and barium citrateeluate.
 6. The method according to claim 5, wherein said normalizingagent also includes gluconic acid, trehalose, malto dextrin and barbitalbuffered saline.
 7. The method according to claim 1, wherein each ofsaid plurality of conduits are disposed within a common cuvette.
 8. Themethod according to claim 7, further including the steps of:pricking thefinger of a patient with a lancet to draw blood; discarding a firstdroplet of blood formed on the finger; transferring a second droplet ofblood formed on the finger to the cuvette,wherein the second droplet ofblood can be drawn into the plurality of conduits.
 9. The methodaccording to claim 7, further including the steps of:drawing blood froma patient with a lancet; placing a sample of the drawn blood in areservoir device; coupling the reservoir device to the cuvette, whereinthe blood can be drawn into the plurality of conduits from thereservoir.
 10. The method according to claim 9, wherein said reservoirdevice is coupled to said lancet and said step of coupling the reservoirdevice to the cuvette includes bringing the lancet in contact with thecuvette.
 11. The method according to claim 1, wherein said normalizingagent includes Vitamin K dependent clotting factor concentrate, bariumcitrate eluate, trehalose, malto dextrin and barbital buffered saline.12. The method according to claim 11, wherein said normalizing agentfurther includes gluconic acid.
 13. The method according to claim 11,wherein said normalizing agent further includes heparin.
 14. The methodaccording to claim 11, wherein said normalizing agent includes1.0μ/ml-3.5μ/ml Vitamin K dependent clotting factor concentrate,0.009μ/ml-0.05μ/ml barium citrate eluate, 0.008M-0.03M gluconic acid,3.0%-8.0% trehalose and 2.0%-6.0% malto dextrin.
 15. A method ofperforming a prothrombin time test on a blood sample, comprising thesteps of:providing a plurality of conduits that extend from a first endto a second end, wherein at least one restriction is disposed betweensaid first end and second end in each of said conduits, said pluralityof conduits including at least one test conduit and at least one controlconduit; providing an anticoagulant in said at least one controlconduit, wherein said anticoagulant is capable of producing an abnormalblood sample with abnormal coagulation characteristic when mixed withthe blood sample; drawing a predetermined volume of blood into each ofsaid plurality of conduits; simultaneously moving the blood in each ofsaid plurality of conduits back and forth through said at least onerestriction from a first position to a second position, wherein saidanticoagulant in said control conduit mixes with the blood and createssaid abnormal blood sample; timing how long it takes the blood in eachof said test conduits to move from said first position to said secondposition, until a predetermined degree of coagulation occurs; analyzingthe coagulation times occurring said test conduit, to obtain arepresentative prothrombin time for the blood sample; and using theabnormal blood sample in the control conduit as a quality control sampleto quantify the reliability of the prothrombin time test for the bloodsample.
 16. The method according to claim 15, further including the stepof mixing the blood in each of said plurality conduits with aprothrombin time reagent.
 17. The method according to claim 16, whereinsaid prothrombin time reagent is selected from a group including tissuethromboplastin, extract and tissue factor.
 18. The method according toclaim 15, further including the steps of:mixing the blood in one of saidconduits with a normalizing agent that counteracts the effects of ananticoagulant in the blood sample, thereby creating a normalized bloodsample with generally normal coagulation characteristics; using thenormalizing blood sample in the prothrombin time test as a qualitycontrol sample to quantify the reliability of the prothrombin time testfor the blood sample.
 19. The method according to claim 18, wherein saidnormalizing agent includes Vitamin K dependent clotting factorconcentrate and barium citrate eluate.
 20. The method according to claim5, wherein said normalizing agent also includes gluconic acid,trehalose, malto dextrin and barbital buffered saline.
 21. The methodaccording to claim 15, wherein each of said plurality of conduits aredisposed within a common cuvette.
 22. The method according to claim 21,further including the steps of:pricking the finger of a patient with alancet to draw blood; discarding a first droplet of blood formed on thefinger; transferring a second droplet of blood formed on the finger tothe cuvette, wherein the second droplet of blood can be drawn into theplurality of conduits.
 23. The method according to claim 21, furtherincluding the steps of:drawing blood from a patient with a lancet;placing a sample of the drawn blood in a reservoir device; coupling thereservoir device to the cuvette, wherein the transferring a seconddroplet of blood formed on the finger to the cuvette, wherein the bloodcan be drawn into the plurality of conduits from the reservoir.
 24. Themethod according to claim 23, wherein said reservoir device is coupledto said lancet and said step of coupling the reservoir device to thecuvette includes bringing the lancet in contact with the cuvette.